The design of catalysts for transition metal-mediated reactions is an active field in chemistry in the 21st century. It has been well recognised that ligands employed in these processes have a significant impact on the outcome of the reactions. The design and application of ligands in homogeneous catalysis reactions were the overarching aims of this project. Two areas were explored in this project, on the ligand synthesis side: 1. The use of directed ortho metallation (DoM) technology to synthesise unsymmetrical phosphines. 2. The synthesis of sterically hindered phosphines and their application to transition metal-mediated reactions. For the first sub-project, a range of N,N-dialkyl-diphenylphosphinic amides was synthesised in near quantitative yields. Deprotonation with s-BuLi and quenching the anion formed in the reaction with a range of electrophiles resulted in the desired ortho-substituted products in good yields. Differentiation of the second aromatic ring was possible, if the isolated mono-substituted products were used in further DoM reactions as starting materials. This methodology provided a range of highly substituted unsymmetrical phosphinic amides. Incorporation of other directing groups can change the selectivity of subsequent DoM reactions providing efficient routes to 2,2’ and 2,6-disubstituted products. Hydrolysis of the phosphinic amide moiety to the phosphinic acid with aqueous HCl, chlorination (SOCl2) and reaction of the acid chloride with a range of Grignard reagents provided an efficient method for the conversion of the phosphinic amide into a P-chirogenic but racemic phosphine oxide. Known methodology can convert this phosphine oxide into a phosphine that can be applied to transition metal catalysed reactions. This methodology provides an effective method for the synthesis of highly functionalised unsymmetrical phosphines. The approach facilitated substantial modifications to the ligand, which allows for efficient tailoring thereof for the metal-mediated reaction in which it is to be used. In the second sub-project, the DoM reaction was again employed but with (diaryl or dialkyl) phosphines as electrophilic quenches, resulting in the isolation of sterically hindered phosphines. Comparison between the ligands was made using the palladium-catalysed Suzuki reactions (catalytic approaches), Vaska type complexes (electronic effects) and phosphine selenium coupling constants (stereo-electronic effects). It was concluded that steric bulk and electronic characteristics affect the activity of catalysts formed from the ligands of this study, in line with the literature. The ligands were successfully applied to the palladium-catalysed Suzuki reaction using strongly deactivated aryl bromides and also some activated aryl chlorides as substrates at low (0.1% Pd) catalyst loadings. Significant improvements in catalytic activity were observed as the project progressed, using a structure-activity study as a guide. / Prof. D.B.G. Williams

M.Sc. / The objective of the project described in this dissertation was the preparation of a range of bulky electron-rich phosphine ligands making use of the directed ortho metallation (DoM) methodology developed in our labs. These ligands would then be employed in the Suzuki and Heck reactions of aryl bromides and aryl chlorides. A range of phosphinic amides were synthesised with various structural differences. These phosphinic amides all showed high activity in the DoM reaction when using TMSCl and MeI as electrophiles, by successfully incorporating TMS and Me groups in the ortho-positions of these phosphinic amide systems. A phosphonic amide was also synthesised and used in the DoM reaction, and also successfully incorporated TMS and Me in the ortho-position of this system. The success of these reactions was encouraging and provided a route to incorporate a phosphine on the ortho-position of these phosphinic amide and phosphonic amide systems by using a range of phosphine electrophiles Ar2PCl. The route was versatile and various electrophiles were used to prepare phosphine ligands with varying electronic and steric properties. These electrophiles were prepared from PCl3 and the corresponding Grignard reagent. Vaska-type complexes and phosphine selenium coupling constants were used to determine the electronic and stereo-electronic characteristics of the prepared ligands. The phosphine ligands prepared in this project making use of our DoM methodology were tested in the Suzuki cross-coupling reactions and Heck arylation reactions of aryl bromides and aryl chlorides and showed good reactivity with most of the substrates used. An advantage of the ligands prepared is that these ligands are oxidatively and hydrolytically stable

M.Sc. / The main objective of the research described in this dissertation was to prepare several logical series of ligands, being variously substituted at different positions of the aryl ring attached to the P atom. These ligands were evaluated by several techniques including 31P NMR shift measurements, 31P-77Se NMR coupling constant measurements, CO stretching frequency measurements in rhodium(I) Vaska-type complexes of the ligands, application of the ligands in the Rh-catalysed hydroformylation reaction, X-ray studies on single crystals of some of the ligands and computational studies all with the view to establish if phosphorus atoms in arylphosphines could be used as a handle to probe steric and electronic effects of aromatic systems. A series of triarylphosphine ligands containing either ester, fluoro, nitrile, tolyl or a combination of functional groups was prepared by reacting Grignard- or organolithium reagents with P-Cl reagents. The results of this aspect of the work showed that, under the right reaction conditions, these organometal reagents can tolerate certain functional groups. On evaluation of these ligands with the different techniques described above it was found that: 31P NMR shift measurements cannot be used in correlations with the data from the other methods of evaluation used in this study, 31P-77Se coupling constant measurements and CO stretching frequency measurements in rhodium(I) Vaska-type complexes of the ligands can be correlated to a relatively good extent with Rhcatalysed hydroformylation reaction results (provided that ortho-substituted phosphine data are disregarded), 31P-77Se NMR coupling constant measurements and CO stretching frequency measurements in rhodium(I) Vaska-type complexes of the ligands correlated well with computational studies, and finally, computational studies at the level of theory used in this dissertation also correlate quite well with the Rh-catalysed hydroformylation reaction results. In all it was found from this study that the phosphorus atom in arylphosphines can be used as a handle to probe the electronic and steric effects of aromatic systems, and that the most versatile method of ligand evaluation were the 31P-77Se coupling constant measurements and CO stretching frequency measurements in rhodium(I) Vaska-type complexes.

M.Sc. / This study focused on the synthesis and evaluation of phosphine ligands with multiple functional ities. Polar ligands suitable for use in homogeneous catalysis in aqueous/organic systems were synthesised, as were ligands incorporating a boron atom in an intramolecular Lewis acid-Lewis base interaction with the phosphorus atom. A malonate moiety was readily incorporated into a phosphorus starting material, and derivatives were obtained by reduction of the ester groups. The polar diol products were reacted with 1,4-butanesultone which made them water soluble and thus ideal for biphasic catalysis. Wittig chemistry was employed to introduce alkenes of varying electronic nature into a phosphorus-containing aldehyde starting material. The catalysed hydroboration reaction making use of diboron reagents was used to introduce a boron functionality into the resulting a, n-unsaturated ester phosphine I igands. All of the ligands produced were tested in transition metal-catalysed reactions, namely the Heck reaction, the Suzuki reaction, the Stille reaction, the carboxymethylation reaction and the hydroformylation reaction. The polar and water soluble ligands all showed comparable or improved yields to the standard benchmark triphenylphosphine ligand in organic, biphasic and ionic liquid media. The electronic nature of the alkene ligands largely dictated the activities observed in the Heck, Suzuki and Stille reactions. The electron rich ligands showed improved activities in the Heck reaction, while the electron poor ligands showed improved activities in the Suzuki reaction. In contrast, the Stille reaction seemed to be more affected by the steric demands of the ligands rather than by electronic considerations. It was also found that the boron containing ligands showed an enhanced activity in comparison to the boron free unsaturated and saturated ester ligands. This enhancement was directly ascribable to the Lewis acidic boron atom. This study allowed the synthesis of a range of functionally varying phosphine ligands which where shown to influence transition metal-catalysed reactions based specifically on the functionality present.

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